Genome-wide Association Study for the Identification of Genetic Risk Factors of Periodontitis

牙周炎是一种口腔黏膜屏障和牙齿支持组织的慢性炎症性疾病。分为慢性牙周炎(CP)和侵袭性牙周炎(AGP)。CP多见于成人，以疾病进展缓慢为特征，而AGP见于年轻人，其诊断依据是牙槽骨快速附着丧失和破坏。一些环境和生活方式因素在牙周炎的病因学中起着重要作用，但这些因素并不总是导致疾病，而且也有易感和耐受的个体。人们认为，遗传因素在疾病病因学中起着基础性作用，特别是在最严重的表型中。多年来，正式的遗传学研究证实了帕金森病的遗传基础，但至今只有一小部分遗传性得到了解释。有趣的是，冠状动脉疾病(CAD)和类风湿性关节炎(RA)与PD的高发病率相关，提示PD可能有一定的病因作用。本研究的目的是阐明帕金森病的遗传结构，识别帕金森病的遗传危险因素，并与冠心病或类风湿性关节炎共享。为此，它的目标是使用Illumina OmniExpess阵列对624例德国AGP病例和现有的GWAS数据集进行全基因组关联研究(GWAS)，这些数据集包括6,000个德国对照。重要的关联将通过全基因组单SNP关联测试、全基因显着性测试和通径分析来选择。我们将进一步开发针对600例德国AGP病例和3,000名德国对照的定制基因分型阵列Exomecip(Illumina)的现成基因型数据集，以及各种公认的CAD和RA的基因组范围关联研究(GWAS)数据集。将在另外600例欧洲AGP病例和另一例土耳其AGP病例和对照中复制选定的重要SNP关联。复制的单核苷酸多态(SNPs)关联随后将在1,200例CP病例和2,500名对照的德国样本中得到验证。我们的进一步目标是通过对给出最强关联证据的选定区域进行有针对性的重新测序来确定假定的功能变体。它们在疾病病因学中的作用随后将在完整的AGP和CP病例对照样本的大规模重复研究中得到验证。预期的结果将对了解疾病相关的分子途径以及开发新的诊断工具和治疗模式具有重要意义。

Periodontitis (PD) is a chronic inflammatory disease of the oral mucosal barrier and the supporting tissues of the teeth. It is classified into the sub-forms chronic periodontitis (CP) and aggressive periodontitis (AgP). Whereas CP is mostly observed in adults and is characterized by a slow progress of the disease, AgP is found in young individuals and is diagnosed based on rapid attachment loss and destruction of the alveolar bone. Several environmental and life-style factors play a significant role in the aetiology of periodontitis, but these factors do not always lead to disease and there are susceptible and tolerant individuals. It is believed that genetic factors play a fundamental role in disease aetiology, particularly in the most severe phenotypes. The genetic basis of PD was demonstrated by formal genetic studies since many years but only a fraction of the heritability has yet been explained. Interestingly, coronary artery disease (CAD) and rheumatoid arthritis (RA) are associated with a higher incidence of PD, and it was suggested that PD may have some causal role. The objective of this research proposal is the elucidation of the genetic architecture of PD and the identification of genetic risk factors of PD, which are shared with CAD or RA. To this end, it is aimed to perform a genome-wide association study (GWAS) with 624 German AgP cases and existing GWAS data-sets of > 6,000 German controls using Illumina OmniExpess Arrays. Significant associations will be selected by genome-wide single-SNP association tests, gene-wide significance tests, and pathway analysis. We will further exploit readily available genotype-data sets of the custom genotyping array Exomechip (Illumina) for 600 German AgP cases and 3,000 German controls, and of various imputed genome-wide association study (GWAS) data sets of CAD and RA. Replication of selected significant SNP associations will be performed in an additional sample of further 600 European AgP cases and in an additional sample of Turkish AgP cases and controls. Replicated single nucleotide polymorphisms (SNPs) associations will be subsequently validated in a German sample of 1,200 CP cases and 2,500 controls. We further aim to identify the putative functional variants by targeted resequencing of selected regions that give the strongest evidence of association. Their role for disease aetiology will subsequently be validated in a large scale replication study in the complete AgP and CP case-control samples. The expected results will be important for the understanding of the disease relevant molecular pathways and for the development of new diagnostic tools and treatment modalities.